P804: PLASMA CELL LEUKEMIA-LIKE TRANSCRIPTOME OF BONE MARROW PLASMA CELLS AND CIRCULATING TUMOR CELL LEVELS IN PERIPHERAL BLOOD COMPLEMENTARILY DEFINE HIGH-RISK IN NEWLY DIAGNOSED MULTIPLE MYELOMA
Authors: Mattia D’agostino, Davine Hofste Op Bruinink, Mark van Duin, Delia Rota-Scalabrini, Luca Bertamini, Rowan Kuiper, Angelo Belotti, Vincenzo Marasco, Stefania Oliva, Elena Rivolti, Jennifer Rogers, Roberto Mina, Mariella Grasso, Antonio Ledda, Massimo Offidani, Monica Galli, Michele Cavo, Annemiek Broijl, Pellegrino Musto, Benedetto Bruno, Mario Boccadoro, Pieter Sonneveld, Francesca Gay
Journal: HemaSphere (2023)

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: Despite the introduction of many effective treatment options for newly diagnosed multiple myeloma (NDMM), a subgroup of high-risk patients remains challenging to treat. Early identification of these patients is essential to enable enrollment in risk-adapted trials. Recently, two novel high-risk markers have been established with independent prognostic value in the context of conventional prognostic tools in NDMM: (1) high levels of circulating tumor cells (CTCs) in peripheral blood (PB), defined by a threshold of >0.07% (Bertamini et al, JCO 2022); (2) plasma cell leukemia-like (PCL-like) status of bone marrow (BM) tumor cells, defined by a combined transcriptomic score of 54 genes (Hofste op Bruinink et al, JCO 2022). Even though PCL-like status is associated with high CTC levels, it remains unclear if these markers have complementary prognostic value. Aims: To assess if PCL-like status and high CTC levels have independent prognostic value in a combined model with conventional risk markers in NDMM. Methods: At baseline, both PCL-like status and CTC levels were determined in transplant-eligible NDMM patients enrolled in the phase 2, randomized controlled FORTE trial (NCT02203643). Off label use of drugs was involved. All patients provided informed consent and received carfilzomib-based induction-consolidation with or without transplant and maintenance with lenalidomide with or without carfilzomib. RNA Seq data of CD138-enriched BM tumor cells were generated within the framework of the MMRF CoMMpass study (NCT01454297). CTC quantification was performed with multiparameter flow cytometry (sensitivity 4×10–5). Progression-free survival (PFS) and overall survival (OS) were analyzed, hazard ratios (HRs) for PCL-like status and CTC levels were estimated using a Cox proportional hazards model including both markers and adjusted for ISS, cytogenetic risk, LDH levels and first randomization arm. Results: Transcriptomic data were available of 122 patients. PCL-like status was found in 33/122 (27%) patients, with the remainder being classified as intramedullary MM (i-MM). PCL-like status was associated with a higher rate of LDH levels above the upper limit of normal (30% in PCL-like MM vs 9% in i-MM, P=0.007), while no statistically significant differences in the distribution of ISS, cytogenetic risk [del(17p) or t(4;14) or t(14;16)], gain(1q), amp(1q), R2-ISS group or randomization arm were found. Of 95/122 (78%) NDMM patients, baseline CTC levels were also available. PCL-like MM patients had higher CTC levels (median 0.97%, interquartile range [IQR] 0.28%–1.62%) than i-MM patients (median 0.03%, IQR 0.01%–0.14%, P<0.001). In the PCL-like cohort, 74% of patients had high CTC levels, as compared with 36% in the i-MM cohort (P=0.002). After a median follow-up of 68 months, in a multivariate model for PFS, both PCL-like status (HR 2.18, 95% CI 1.16–4.11, P=0.016) and high CTC levels (HR 2.20, 95% CI 1.09–4.47, P=0.028) retained independent prognostic value. Combining these two factors, median PFS was not reached in i-MM patients with low CTC levels, 54.2 months in PCL-like MM with low CTC levels, 37.9 months in i-MM with high CTC levels and 23.5 months in PCL-like MM with high CTC levels (Figure). In a multivariate model for OS, a statistically significant effect was found for PCL-like status (HR 3.12, 95% CI 1.26–7.69, P=0.014), while a borderline significant effect was found for high CTC levels (HR 2.88, 95% CI 0.93–8.96, P=0.068). Summary/Conclusion: PCL-like status and high CTC levels are complementary prognostic markers to define high-risk disease in a cohort of transplant-eligible NDMM patients.Keywords: Multiple myeloma, High risk, Plasma cells, Transcription